PROJECT SUMMARY/ABSTRACT This proposal describes a training program to advance my academic career in the study of the tumor suppressive barriers that are bypassed during progression to malignancy and how they can be restored for therapeutic benefit in established tumors. Cellular senescence, a tumor suppressive process involving durable cell cycle arrest and activation of a senescence-associated secretory phenotype (SASP), can recruit immune cells to target and clear tumors. During my postdoctoral work, I identified molecularly targeted agents that can reestablish senescence, SASP, and a unique form of Natural Killer (NK) immune surveillance that drives tumor regressions and long-term survival in KRAS mutant lung cancer. This research proposal aims to characterize and exploit the SASP to sustain immune and stromal control of RAS-driven solid tumors, with the goal of identifying new or potentiating existing therapies for these deadly diseases. My expertise in mouse modeling, target discovery, and the biology of senescence and immune surveillance that I have acquired during my postdoctoral studies puts me in a unique position to significantly contribute to elucidating the role of senescence in cancer therapy and identifying new therapeutic strategies for KRAS mutant tumors. To accomplish the research outlined in this application, I will leverage modular and immune competent mouse models of KRAS mutant lung and pancreas cancer, as well as methods to reestablish senescence, SASP, and NK cell immune surveillance that I have already developed in the Lowe lab. In Aim 1, with the hypothesis that methods to overcome NK cell dysfunction are needed to establish disease control, I will explore mechanisms and strategies to further potentiate NK cell responses in KRAS mutant lung cancer through transcriptional and immune profiling and functional screening. In Aim 2, the organ-specific and pleiotropic effects of the SASP on tumor-stromal interactions in pancreas tumors will be interrogated to determine SASP factors necessary for productive tumor control and how they impact the efficacy of standard-of-care therapies. Together, these approaches will unveil new ways by which the SASP can be used to control KRAS-driven tumors. To achieve the goals of this award, I will be mentored by Dr. Scott Lowe and guided by an exceptional advisory committee I have established at MSKCC. Dr. Lowe is an internationally recognized expert in cancer biology, and is focused on understanding tumor suppressor networks through the use of sophisticated mouse models. The advisory committee, constituted by Dr. Lowe, Dr. Sun, Dr. Rosen, Dr. Iacobuzio-Donahue, and Dr. Rudin will monitor and support my transition to independence. Moreover, they will provide invaluable guidance during the process of applying and interviewing for faculty positions. MSKCC will provide me institutional support, including resources for experimental work and career development, as well as an engaging scientific environment. My objective is to obtain a faculty position to develop an impactful research program, where the K99/R00 funding mechanism will serve as an essential step in my transition to independence in academia. ! ! !